Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non-Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair.
Genetic susceptibility to therapy-related leukemia after Hodgkin lymphoma or non-Hodgkin lymphoma: role of drug metabolism, apoptosis and DNA repair.
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DOI：
10.1038/bcj.2012.4
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发表时间：
2012-03
影响因子：
12.8
通讯作者：
Bhatia, S.
中科院分区：
文献类型：
--
作者：
Ding, Y.;Sun, C-L;Li, L.;Li, M.;Francisco, L.;Sabado, M.;Hahn, B.;Gyorffy, J.;Noe, J.;Larson, G. P.;Forman, S. J.;Bhatia, R.;Bhatia, S.
治疗相关的骨髓增生异常或急性髓系白血病 (t-MDS/AML) 是霍奇金淋巴瘤 (HL) 或非霍奇金淋巴瘤 (NHL) 患者非复发死亡的主要原因。 1 t-MDS/AML 与接触烷化剂和拓扑异构酶 II 抑制剂有关。这些药物引起的 DNA 损伤事件引发抗肿瘤活性所需的细胞凋亡；有时，染色体损伤的不完全修复会导致染色体畸变，从而导致白血病发生。接触任何特定的基因毒性物质后，t-MDS/AML 风险的个体间差异表明遗传易感性的作用。此外，t-MDS/AML 与新发 MDS/AML 具有形态学和遗传相似性，2 表明治疗相关型和新发 MDS/AML 可能具有相同的遗传易感位点。之前的研究基本上没有结论，主要是因为关注的是单个基因。 3, 4 在同时检查多个基因的少数研究中，具有一种以上风险变异的个体风险较高。 5, 6 我们假设药物代谢、细胞凋亡、DNA 合成、甲基化和修复途径的关键基因以及参与新发 AML 的基因中编码的遗传变异，7 可能会增加 t-MDS/AML 的风险。通过基因型和基因表达分析，我们研究了这些途径中的个体遗传变异是否会改变暴露于基因毒性药物的 HL 或 NHL 患者发生 t-MDS/AML 的风险（图 1）。我们还测试了细胞凋亡和其他假设途径之间的协同作用。接受常规疗法或自体造血细胞移植 (aHCT) 治疗 HL 或 NHL 的患者构成了本病例对照研究的抽样框架。病例 (n= 49) 包括随后发展为 t-MDS/AML 的患者。对照组（n = 49）来自同一抽样框架，没有 t-MDS/AML，并使用以下标准与病例进行匹配：初次诊断（HL 或 NHL）、初次诊断时的年龄和初次诊断的年份、诊断后的随访时间（对照组更长）和遗传血统。为了进一步完善遗传血统匹配，我们使用 STRUCTURE 2.0（参考文献 8）根据 51 个信息标记（AIM）9（补充方法和补充表 1）估计研究对象的血统组成。研究人员对来自 12 名 NHL 病例和 22 名匹配对照的外周血干细胞 (PBSC) 自体移植物的造血干/祖细胞 (HSC) 的基因表达模式进行了研究。希望之城的人类受试者保护委员会批准了该方案。根据赫尔辛基宣言提供知情同意。对于每位研究参与者，计算了累积治疗暴露量，如补充方法中详述。研究对象的人口统计学和临床特征总结于补充表2中。
Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a major cause of non-relapse mortality in patients treated for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). 1 t-MDS/AML is associated with exposure to alkylating agents and topoisomerase II inhibitors. The DNA-damaging events caused by these agents initiate apoptosis required for antineoplastic activity; occasionally, imperfect repair of chromosomal damage results in chromosomal aberrations, leading to leukemogenesis.The inter-individual variability in the risk of t-MDS/AML for any given exposure to genotoxic agents suggests the role of genetic susceptibility. In addition, t-MDS/AML shares morphological and genetic similarity with de novo MDS/AML, 2 suggesting that therapy-related and de novo MDS/AML may share genetic susceptibility loci. Previous studies have been largely inconclusive, primarily because of the focus on single genes. 3, 4 In the few studies where multiple genes were examined simultaneously, individuals with more than one risk variant were at higher risk. 5, 6 We hypothesized that genetic variations encoded in key genes in the pathways of drug metabolism, apoptosis, DNA synthesis, methylation and repair, as well as genes involved in de novo AML, 7 could potentially contribute to the risk of t-MDS/AML. Using both genotype and gene expression analyses, we investigated whether individual genetic variability in these pathways modify the risk of t-MDS/AML in patients with HL or NHL exposed to genotoxic agents (Figure 1). We also tested for synergy between apoptosis and other hypothesized pathways. Patients treated with conventional therapy or autologous hematopoietic cell transplantation (aHCT) for HL or NHL formed the sampling frame for this case-control study. Cases (n= 49) consisted of patients who subsequently developed t-MDS/AML. Controls (n= 49) were drawn from the same sampling frame, did not have t-MDS/AML and were matched to cases using the following criteria: primary diagnosis (HL or NHL), age at primary diagnosis and year of primary diagnosis, length of follow-up from diagnosis (longer for controls) and genetic ancestry. To further refine matching on genetic ancestry, we used STRUCTURE 2.0 (ref. 8) to estimate ancestry composition of study subjects based on 51 informative markers (AIM) 9 (Supplementary Methods and Supplementary Table 1). Gene expression patterns were studied in hematopoietic stem/progenitor cells (HSC) from peripheral blood stem cell (PBSC) autografts from a subset of 12 NHL cases and 22 matched controls. The Human Subjects Protection Committee at City of Hope approved the protocol. Informed consent was provided according to the Declaration of Helsinki. For each study participant, cumulative therapeutic exposures were calculated, as detailed in the Supplementary Methods. Demographic and clinical characteristics of the study subjects are summarized in Supplementary Table 2.
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影响因子：
3.9
作者：
Kosoy, Roman;Nassir, Rami;Tian, Chao;White, Phoebe A.;Butler, Lesley M.;Silva, Gabriel;Kittles, Rick;Alarcon-Riquelme, Marta E.;Gregersen, Peter K.;Belmont, John W.;De La Vega, Francisco M.;Seldin, Michael F.
通讯作者：
Seldin, Michael F.
影响因子：
11.5
作者：
Seedhouse, C;Faulkner, R;Russell, N
通讯作者：
Russell, N
影响因子：
20.3
作者：
Ellis, Nathan A.;Huo, Dezheng;Onel, Kenan
通讯作者：
Onel, Kenan
影响因子：
11.4
作者：
Woo, MH;Shuster, JJ;Relling, MV
通讯作者：
Relling, MV
影响因子：
3.8
作者：
Weisberg, I;Tran, P;Rozen, R
通讯作者：
Rozen, R